In Alzheimer's Disease (AD), the cleavage of beta amyloid protein precursor from the intracellular membrane often produces a protein AB-42 which is incompletely removed by normal clearance processes. Over time, this protein is deposited as a beta amyloid protein Aβ plaque within brain tissue, leading to the local destruction of neurons. The Aβ plaque deposition is also believed to provoke an inflammatory response by microglia and macrophages. These cells are believed to respond to the plaque deposition by releasing pro-inflammatory cytokines and reactive oxygen species (ROS). Although the inflammatory response may be provoked in an effort to clear the brain tissue of the detrimental plaque, it is now believed that this inflammation also injures local neuronal tissue, thereby exacerbating AD.
High levels of aluminum, copper, iron, and zinc have been found in the brains of AD patients. For example, Finefrock, J. Am. Geriatr. Soc., 51, 1143-1148, (2003) reports the following concentrations:
Total Amyloid PlaqueAD NeuropilControl neuropilMetal(ug/g)(ug/g)(ug/g)Copper251904Iron533919Zinc695123Aluminum———It has been hypothesized by Finefrock, supra, that age-related dyshomeostasis and environmental accumulation are responsible for these high metal levels.
Furthermore, it is believed that these heavy metals play a critical role in the precipitation of BAP. It is known that BAP binds to these heavy metals and even has highly specific binding sites for copper. Accordingly, high levels of these heavy metals have been found in BAP plaques. Huang, J. Nutrition, 2000, May 130(5S Supp.) 1488S-92S).
Moreover, since both copper and iron are redox active, these metal-laden deposits act as catalysts for cell-free redox reactions that generate hydrogen peroxide and consequently highly toxic hydroxyl radical.
Accordingly, it is believed that higher-than-normal levels of heavy metals in the brain are deleterious because they not only promote the deposition of BAP plaques, a portion of them promote oxidative stress when deposited.
Aluminum is of particular concern. It has long been hypothesized that aluminum plays a critical role in the pathogenesis of AD, although this point has remained controversial. Nonetheless, according to Gupta, Cell Mol. Life Sci., 2005 January 62(2) 143-58, the neurotoxic effects of aluminum are beyond any doubt. Moreover, it has further been reported that, once it has entered the brain, aluminum is fairly persistent. Yokel, Toxicol. Sciences, 64, 77-82 (2001) has hypothesized an aluminum half-life in the rat brain of about 150 days, and in the human brain of about 12 years. According to Yokel, supra, repeated aluminum exposure paired with aluminum persistence produces aluminum accumulation. Therefore, the neurotoxicity and the long-half life of aluminum have made it a potential therapeutic target for AD.
Because it has been proposed that these heavy metals are a key lynchpin in the progression of AD, there have been numerous attempts to remove these heavy metals from brain tissue. The use of chelating agents such as desferrioxamine (DFO) and clioquinol has been investigated, and it has been found that these agents are effective in removal. See Finefrock, J. Am. Geriatr. Soc., 51, 1143-1148, (2003). Yokel, Toxicol. Sciences, 64, 77-82 (2001) has reported that significant reduction of aluminum accumulation and effective treatment of aluminum toxicity requires prolonged DFO therapy. However, it has also been found that these chelating agents have many drawbacks, including systemic toxicity, significant discomfort during application (intramuscular injection ten times a week for two years), and non-specificity of metallic removal.